The improvements which have been made in recent years in the treatment of cancer in man has been the direct result of the development of protocols using a combination of drugs given in a proper schedule. The advantages of combination chemotherapy are several-fold and include independent organ toxicities, effective cell-kill for tumor cells in different phases of the cell cycle, the decrease in the development of drug resistance which is prevelant with single drug therapy and the possibility of synergistic response from the multiple drug regimen. Ribonucleotide reductase is the key enzyme in the formation of the deoxyribonucleotide precursors of DNA. This enzyme has been a site for which several drugs have been developed as potential antitumor agents. These have included hydroxyurea, the thiosemicarbazones and the nucleoside dialdehydes. Our recent results have shown that we can separate the mammalian ribonucleotide reductase from Ehrlich tumor cells into two non-identical components, neither of which have reductase activity. However, the combination of the two components generates reductase activity. We have also shown that each of the components can be specifically and independently inactivated by different types of inhibitors. preliminary data have been obtained which strongly suggest that the same can be obtained in intact cells. This system, the mammalian ribonucleotide reductase, offers an excellent model to study combination chemotherapy in which the specific inhibitors are directed at the individual components of a single enzyme.